A biomarker generally has a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. See Atkinson et al., 2001, Clin. Pharmacol. Ther. 69:89-95. Biomarkers vary widely in nature, ease of measurement and correlation with physiological states of interest. See, e.g., Frank et al., 2003, Nature Reviews Drug Discovery 2:566-580. It is widely believed that the development of new validated biomarkers will lead both to significant reductions in healthcare and drug development costs and to significant improvements in treatment for a wide variety of diseases and conditions. Thus, a great deal of effort has been directed to using new technologies to find new classes of biomarkers. See, e.g., Petricoin et al., 2002, Nature Reviews Drug Discovery, 1:683-695; and Sidransky, 2002, Nature Reviews Cancer 2:210-219; Ludwig and Weinstein, 2005, Nature Reviews Cancer 5:845-856; Lee et al., 2007, Adv. Cancer. Res., 96:269-298; Dhani and Siu, 2008, Cancer Metastasis Rev. 27:339-349; Carden et al., 2009, Clin. Pharmacol. Ther. 85:131-133.
The interactions of cell surface membrane components play crucial roles in transmitting extracellular signals to a cell in normal physiology and in disease conditions. In particular, many types of cell surface receptors undergo dimerization, oligomerization or clustering in connection with the transduction of an extracellular event or signal into a cellular response, such as, e.g., proliferation, increased or decreased gene expression or the like. See, e.g., George et al., 2002, Nature Reviews Drug Discovery 1:808-820; Mellado et al, 2001, Ann. Rev. Immunol. 19:397-421; Schlessinger, 2000, Cell 103:211-225; and Yarden, 2001, Eur. J. Cancer 37:S3-S8. The role of such events in diseases, such as cancer, has been the object of intense research and has led to the development of several new drugs and drug candidates. See, e.g., Herbst and Shin, 2002, Cancer 94:1593-1611; Yarden and Sliwkowski, 2001, Nature Reviews Molecular Cell Biology 2:127-137; McCormick, 1999, Trends in Cell Biology 9:53-56 (1999); and Blume-Jensen and Hunter, 2001, Nature 411:355-365.
Expression levels of individual cell surface receptors, such as Her-2 in breast cancer, have been used as biomarkers, especially to determine patient prognosis or whether a patient will or will not respond to certain treatments. In addition, oncogenic tyrosine kinases such as members of the epidermal growth factor receptor family have provided targets for drug development. However, the tyrosine kinase inhibitors targeted to EGFR and Her-2 have shown less clinical efficacy than anticipated from promising preclinical studies, which has led to interest in other EGFR-family members, such as Her-3, in part for prognostic value as biomarkers and in part because of interactions with other family members, leading to potential new drug targets. See Menendez and Lupu, 2007, Breast Cancer Research 9:111; Lee-Hoeflich et al., 2008, Cancer Res 68:5878-5887; Fuchs et al., 2006, Anticancer Res. 26:4397-4402; Sergina et al., 2007, Nature 445:437-441; and Tovey et al., 2006, J. Pathol. 210:358-362.
Her-3 is sometimes over-expressed in breast cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, non-small cell lung cancer, melanoma, pharyngeal cancer, pancreatic cancer, esophageal cancer, glioma, biliary tract carcinoma, cholangiocarcinoma, gastric cancer, endometrial cancer, gall bladder cancer, squamous cell carcinoma or basal cell carcinoma. Conventional immunohistochemical (IHC) or fluorescence in situ hybridization (FISH) analyses have been used to detect Her-3 over-expression. Unfortunately, IHC and FISH have certain limitations as diagnostic tools in that they are not necessarily accurate and also prone to different interpretations by different laboratory personnel. There are currently no methods for accurately assessing the level of Her-3. The advent of a quantitative method for measuring Her-3 would facilitate the ability to accurately determine a cancer patient's prognosis and/or whether a patient is likely to respond to a certain treatment. See Mosesson et al., 2004, Semin. Cancer. Biol. 14:262-270.